TRPML1调控“自噬-ROS-LTP”轴参与吗啡耐受及其机制的研究

阿片类止痛药有有害的副作用，包括镇痛耐受和阿片诱导的痛觉过敏。吗啡启动这些不适应过程的机制仍有争议。越来越多的证据表明，自噬功能障碍在吗啡耐受中起着关键作用。在前期的工作中，我们发现TRPML1介导的脊髓背角神经元自噬活动障碍促进了耐受和痛觉过敏的发展。利用ML-SI3阻断TRPML1通道可以显著改善吗啡造成的自噬功能障碍，促进线粒体更新，清除有害ROS。而且，ML-SI3可以显著抑制吗啡造成的耐受、痛觉过敏和脊髓水平LTP。基于以上的预实验结果，本项目将进一步采用分子生物学的方法探究TRPML1调控“自噬-ROS-LTP”轴参与吗啡耐受的分子机制。我们期待在不远的将来，TRPML1小分子抑制剂可以作为疼痛治疗的辅助药物用以扩大吗啡的临床应用。

Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia. The mechanisms of morphine act to initiate these maladaptive processes remain disputed. Accumulating evidence suggests that autophagy dysfunction plays a critical role involved in morphine tolerance. We found that, TRPML1 mediated autophagy dysfunction of neurons in the spinal dorsal horn initiate tolerance and hyperalgesia development. Down-regulating TRPML1 with ML-SI3, a TRPML1 specific antagonist, significantly rescued morphine induced autophagy dysfunction, promoted mitochondrial renewal and removed harmful ROS. Moreover, ML-SI3 was sufficient to abrogate morphine tolerance, hyperalgesia and spinal long-term potentiation (LTP). Based on the above preliminary results, this project will further explore the molecular mechanism of TRPML1 regulating “Autophagy-ROS-LTP” axis to participate in morphine tolerance by molecular biology methods. We hope that TRPML1 small molecule inhibitors can be used as adjunctive drugs for pain treatment in the near future to expand the clinical application of morphine.